Summary MDSCsareoneofthemajortypesofimmunecellsthatcontributetotumor-inducedimmunesuppressionand escape from immune elimination. Importantly, MDSCs have been suggested to contribute to resistance to variouscancertherapies,includingtoanti-CTLA-4andanti-PD-1blockade.Hence,targetingMDSCscouldbe anattractiveapproachtomodulatetumorimmunitytoimprovecurrentcancerimmunotherapies.Wehavevery recently reported that phenformin, a mitochondrial respiratory chain complex I inhibitor, selectively reduced proportionofpolymorphonuclearMDSCs(PMN-MDSCs),butnototherimmunecellsinspleensoftumor-bearing mice.PhenforminalsoinhibitedproliferationofPMN-MDSCsderivedfrombonemarrowco-culturedwithtumor cells in vitro. Furthermore, PMN-MDSCs derived from mice treated with phenformin showed attenuated suppressive activities towards CD8+ T cells in T cell proliferation assays. In our unpublished metabolomics profiling studies of PMN-MDSCs, we have uncovered additional potential metabolic vulnerabilities of PMN- MDSCs.Basedonthesefindings,wehypothesizethatPMN-MDSCspossessdistinguishingmetabolicfeatures. GiventheimportantcontributionofMDSCstotumorimmuneescapeandimmunotherapyresistance,wefurther hypothesizethattargetingthemetabolicvulnerabilitiesofPMN-MDSCsmaycooperatewithimmunecheckpoint blockadetounleashTcellresponses,leadingtoimprovedanti-tumorefficacy.Inaim1,weplantocharacterize themetabolicvulnerabilitiesofPMN-MDSCs.WewillnotonlyelucidatemetabolicfeaturesofPMN-MDSCsthat underlietheirsensitivitytophenformin,butalsoidentifyothermetabolictargetsofPMN-MDSCs,suchasthose involvedintheglutaminemetabolism.Inaim2,wewillassessthetherapeuticbenefitofcombiningtargetingthe metabolic vulnerabilities of PMN-MDSCs with immune checkpoint blockade in mouse cancer models. We will evaluatetheeffectsofmetabolicdrugsincombinationwithanti-PD-1blockade,onthetumormicroenvironment andanalyzethecontributionofPMN-MDSCmodulatoryactivityofthesemetabolicdrugsusingthePMN-MDSC adoptivetransferapproach.